The hormone insulin stimulates the uptake of glucose into its target cells by binding to a specific receptor on the cell surface. The insulin receptor (IR) is a so-called receptor tyrosine kinase. Binding of insulin to IR causes the receptor to autophosphorylate tyrosine residues present in its catalytic domains. This activated receptor phosphorylates proteins known as insulin receptor substrates (IRS) on multiple tyrosines. The phosphotyrosines on IRS-1 and -2 then serve as high affinity binding sites for the docking and activation of other intracellular signaling proteins including phosphatidyl-inositol-3'-kinase (PI3-kinase).
The hormone insulin-like growth factor I (IGF-1) is known to have a broad range of effects including promotion of cell survival, stimulation of metabolism, and proliferation of differentiating cells. The receptor to this hormone (IGFR) is also a receptor tyrosine kinase whose activation by IGF-I binding leads to phosphorylation of IRS proteins, and their association with and activation of PI3-kinase, the guanine nucleotide exchange factor Grb2/SOS and mitogen activated protein kinases (MAPKs).
Diabetes mellitus is a condition characterized by hyperglycemia due to a deficiency or reduced effectiveness of insulin, impaired access of insulin to its receptor, inactivation of insulin by antibodies, or receptor defects. Treatment of diabetes in cases of insulin deficiency or severe resistance is by administration of exogenous insulin. However, apart from being expensive, insulin treatment is inconvenient as the exogenous insulin must be injected into the patient. It would be desirable to have a substance capable of bypassing the resistance factor and mimicking the effects of insulin and that could be administered orally.
Several negatively charged polyaromatic compounds that mimic many of the physiological effects of heparin have been identified. These compounds, among which are commercially available synthetic dyes, compete with heparin for binding onto cell surfaces. These compounds have been shown to cause reversal of basic fibroblast growth factor-mediated autocrine cell transformation.sup.(2), modulation of fibroblast growth factor binding to its receptor, angiogenic activity.sup.(3), and antiproliferative activity in vascular smooth muscle cells..sup.(4,5)
International Application in the name of Wher International Holdings discloses anionic polyaromatic compounds that mimic pharmacological activities of glycosaminoglycans. These compounds alter the tissue distribution of biologically active peptides and proteins normally bound to glycosaminoglycans. The compounds are used as anticoagulants, and in the treatment of cardiovascular and neurological disorders.
An example of such an anionic polyaromatic compound is aurintricarboxylic acid (ATA). ATA is capable of forming polymers of variable molecular weight and is known to exhibit a variety of biological activities including inhibition of nucleic acid binding enzymes, platelet aggregation, cytopathogenic effects of HIV-1, and the binding of interferon to its receptor. It is also known to bind to the polynucleotide domains of glucocorticoid receptors and di-hydroxy vitamin D receptors. ATA has been known to protect cells from apoptosis induced by growth factor deprivation or by drugs such as cycloheximide (CX).sup.(1). It has also been shown to increase tyrosine phosphorylation of several proteins in PC12 cells including Shc, PI3-kinase and MAPKs. It has also been shown to induce tyrosine phosphorylation of erbB4 (a member of the epidermal growth factor receptor family).
EB, is an aromatic polysulfated anion that inhibits various DNA polymerases and endonucleases. It has also been shown to inhibit HIV-mediated cytopathogenicity and to enhance the survival of renal tubular epithelial cells exposed to H.sub.2 O.sub.2, and breast cancer cells exposed to CX. EB is known to be non-toxic to humans at high doses.